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VPS13D interacts with VCP/p97 and negatively regulates endoplasmic reticulum–mitochondria interactions

Membrane contact sites (MCSs) between the endoplasmic reticulum (ER) and mitochondria are emerging as critical hubs for diverse cellular events, and alterations in the extent of these contacts are linked to neurodegenerative diseases. However, the mechanisms that control ER–mitochondria interactions...

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Autores principales: Du, Yuanjiao, Wang, Jingru, Xiong, Juan, Fang, Na, Ji, Wei-Ke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351740/
https://www.ncbi.nlm.nih.gov/pubmed/34133214
http://dx.doi.org/10.1091/mbc.E21-03-0097
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author Du, Yuanjiao
Wang, Jingru
Xiong, Juan
Fang, Na
Ji, Wei-Ke
author_facet Du, Yuanjiao
Wang, Jingru
Xiong, Juan
Fang, Na
Ji, Wei-Ke
author_sort Du, Yuanjiao
collection PubMed
description Membrane contact sites (MCSs) between the endoplasmic reticulum (ER) and mitochondria are emerging as critical hubs for diverse cellular events, and alterations in the extent of these contacts are linked to neurodegenerative diseases. However, the mechanisms that control ER–mitochondria interactions are so far elusive. Here, we demonstrate a key role of vacuolar protein sorting–associated protein 13D (VPS13D) in the negative regulation of ER–mitochondria MCSs. VPS13D suppression results in extensive ER–mitochondria tethering, a phenotype that can be substantially rescued by suppression of the tethering proteins VAPB and PTPIP51. VPS13D interacts with valosin-containing protein (VCP/p97) to control the level of ER-resident VAPB at contacts. VPS13D is required for the stability of p97. Functionally, VPS13D suppression leads to severe defects in mitochondrial morphology, mitochondrial cellular distribution, and mitochondrial DNA synthesis. Together, our results suggest that VPS13D negatively regulates the ER–mitochondria MCSs, partially through its interactions with VCP/p97.
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spelling pubmed-83517402021-10-16 VPS13D interacts with VCP/p97 and negatively regulates endoplasmic reticulum–mitochondria interactions Du, Yuanjiao Wang, Jingru Xiong, Juan Fang, Na Ji, Wei-Ke Mol Biol Cell Articles Membrane contact sites (MCSs) between the endoplasmic reticulum (ER) and mitochondria are emerging as critical hubs for diverse cellular events, and alterations in the extent of these contacts are linked to neurodegenerative diseases. However, the mechanisms that control ER–mitochondria interactions are so far elusive. Here, we demonstrate a key role of vacuolar protein sorting–associated protein 13D (VPS13D) in the negative regulation of ER–mitochondria MCSs. VPS13D suppression results in extensive ER–mitochondria tethering, a phenotype that can be substantially rescued by suppression of the tethering proteins VAPB and PTPIP51. VPS13D interacts with valosin-containing protein (VCP/p97) to control the level of ER-resident VAPB at contacts. VPS13D is required for the stability of p97. Functionally, VPS13D suppression leads to severe defects in mitochondrial morphology, mitochondrial cellular distribution, and mitochondrial DNA synthesis. Together, our results suggest that VPS13D negatively regulates the ER–mitochondria MCSs, partially through its interactions with VCP/p97. The American Society for Cell Biology 2021-08-01 /pmc/articles/PMC8351740/ /pubmed/34133214 http://dx.doi.org/10.1091/mbc.E21-03-0097 Text en © 2021 Du et al. “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. https://creativecommons.org/licenses/by-nc-sa/3.0/This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License.
spellingShingle Articles
Du, Yuanjiao
Wang, Jingru
Xiong, Juan
Fang, Na
Ji, Wei-Ke
VPS13D interacts with VCP/p97 and negatively regulates endoplasmic reticulum–mitochondria interactions
title VPS13D interacts with VCP/p97 and negatively regulates endoplasmic reticulum–mitochondria interactions
title_full VPS13D interacts with VCP/p97 and negatively regulates endoplasmic reticulum–mitochondria interactions
title_fullStr VPS13D interacts with VCP/p97 and negatively regulates endoplasmic reticulum–mitochondria interactions
title_full_unstemmed VPS13D interacts with VCP/p97 and negatively regulates endoplasmic reticulum–mitochondria interactions
title_short VPS13D interacts with VCP/p97 and negatively regulates endoplasmic reticulum–mitochondria interactions
title_sort vps13d interacts with vcp/p97 and negatively regulates endoplasmic reticulum–mitochondria interactions
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351740/
https://www.ncbi.nlm.nih.gov/pubmed/34133214
http://dx.doi.org/10.1091/mbc.E21-03-0097
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